EP3737677B1 - Tetrahydroisoquinoline compounds - Google Patents
Tetrahydroisoquinoline compounds Download PDFInfo
- Publication number
- EP3737677B1 EP3737677B1 EP19700284.3A EP19700284A EP3737677B1 EP 3737677 B1 EP3737677 B1 EP 3737677B1 EP 19700284 A EP19700284 A EP 19700284A EP 3737677 B1 EP3737677 B1 EP 3737677B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- alkynyl
- alkenyl
- compound according
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims description 83
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 229910052736 halogen Inorganic materials 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- -1 preferably OH Chemical group 0.000 claims description 35
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 31
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 30
- 125000003342 alkenyl group Chemical group 0.000 claims description 30
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 28
- 125000000304 alkynyl group Chemical group 0.000 claims description 28
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000004122 cyclic group Chemical group 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 201000011510 cancer Diseases 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- 229910052786 argon Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 11
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 102000016914 ras Proteins Human genes 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 0 CCCC*=CNC(C)=* Chemical compound CCCC*=CNC(C)=* 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 102100030708 GTPase KRas Human genes 0.000 description 7
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 7
- 229960004316 cisplatin Drugs 0.000 description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 108700020796 Oncogene Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WFSUZXGEQQDRNQ-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)-2-N-(1,3-oxazol-4-ylmethyl)-7-(2-pyridin-3-ylethoxy)-3,4-dihydro-1H-isoquinoline-2,6-dicarboxamide Chemical compound C1=C(C=CC(=C1C)C1N(CCC2=C1C=C(OCCC1=CC=CN=C1)C(C(=O)N)=C2)C(=O)NCC1=COC=N1)C WFSUZXGEQQDRNQ-UHFFFAOYSA-N 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- DFIGBODBPKTBLL-UHFFFAOYSA-N 6-bromo-1-(2,4-dimethylphenyl)-7-methoxy-3,4-dihydroisoquinoline Chemical compound BrC=1C=C2CCN=C(C2=CC=1OC)C1=C(C=C(C=C1)C)C DFIGBODBPKTBLL-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 231100000590 oncogenic Toxicity 0.000 description 4
- 230000002246 oncogenic effect Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 108700042226 ras Genes Proteins 0.000 description 4
- 108010014186 ras Proteins Proteins 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- RGQCVQNZAIEECL-UHFFFAOYSA-N 3-methoxy-4-[2-(3-phenylmethoxyphenyl)ethoxy]benzaldehyde Chemical compound C(C1=CC=CC=C1)OC=1C=C(CCOC2=C(C=C(C=O)C=C2)OC)C=CC=1 RGQCVQNZAIEECL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 3
- ABFXRHOCVZSBIC-UHFFFAOYSA-N CC1=C(C=CC(=C1)C)C1N(CCC2=CC(=C(C=C12)OC)C(=O)OC)C(=O)OC(C)(C)C Chemical compound CC1=C(C=CC(=C1)C)C1N(CCC2=CC(=C(C=C12)OC)C(=O)OC)C(=O)OC(C)(C)C ABFXRHOCVZSBIC-UHFFFAOYSA-N 0.000 description 3
- CNBZNZQMWGJPCR-UHFFFAOYSA-N FC(C(=O)O)(F)F.CC1=C(C=CC(=C1)C)C1NCCC2=CC(=C(C=C12)OCCC=1C=C(C=CC=1)O)OC Chemical compound FC(C(=O)O)(F)F.CC1=C(C=CC(=C1)C)C1NCCC2=CC(=C(C=C12)OCCC=1C=C(C=CC=1)O)OC CNBZNZQMWGJPCR-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- 102000043276 Oncogene Human genes 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
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- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- BEVPILOCFXAIGU-UHFFFAOYSA-N 1,3-oxazol-4-ylmethanamine;dihydrochloride Chemical compound Cl.Cl.NCC1=COC=N1 BEVPILOCFXAIGU-UHFFFAOYSA-N 0.000 description 2
- HMCUULNSVYRQPS-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)-7-[2-(3-hydroxyphenyl)ethoxy]-6-methoxy-N-(1,3-oxazol-4-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxamide Chemical compound CC1=C(C=CC(=C1)C)C1N(CCC2=CC(=C(C=C12)OCCC1=CC(=CC=C1)O)OC)C(=O)NCC=1N=COC=1 HMCUULNSVYRQPS-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
- JHVALSRTUOVNLL-UHFFFAOYSA-N 2-(3-bromo-4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C(CCN)C=C1Br JHVALSRTUOVNLL-UHFFFAOYSA-N 0.000 description 2
- RHHVCIKVRLMNFC-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)ethanol Chemical compound OCCC1=CC=CC(OCC=2C=CC=CC=2)=C1 RHHVCIKVRLMNFC-UHFFFAOYSA-N 0.000 description 2
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- AMQIPHZFLIDOCB-UHFFFAOYSA-N 3-(2-hydroxyethyl)phenol Chemical compound OCCC1=CC=CC(O)=C1 AMQIPHZFLIDOCB-UHFFFAOYSA-N 0.000 description 2
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- ISQNOILHQYDJPS-UHFFFAOYSA-N 3-[2-[4-(2-aminoethyl)-2-methoxyphenoxy]ethyl]phenol hydrochloride Chemical compound Cl.NCCC1=CC(=C(OCCC=2C=C(C=CC=2)O)C=C1)OC ISQNOILHQYDJPS-UHFFFAOYSA-N 0.000 description 2
- DNEZJKATFHHJEA-UHFFFAOYSA-N 3-[2-[4-[2-[(2,4-dimethylphenyl)methylideneamino]ethyl]-2-methoxyphenoxy]ethyl]phenol Chemical compound CC1=C(C=NCCC2=CC(=C(OCCC=3C=C(C=CC=3)O)C=C2)OC)C=CC(=C1)C DNEZJKATFHHJEA-UHFFFAOYSA-N 0.000 description 2
- YJXJVRVSYQWYLC-UHFFFAOYSA-N 4-(chloromethyl)-2-methoxy-1-[2-(3-phenylmethoxyphenyl)ethoxy]benzene Chemical compound O(CC1=CC=CC=C1)C1=CC(CCOC2=C(OC)C=C(CCl)C=C2)=CC=C1 YJXJVRVSYQWYLC-UHFFFAOYSA-N 0.000 description 2
- ZYUVGYBAPZYKSA-UHFFFAOYSA-N 5-(3-hydroxybutan-2-yl)-4-methylbenzene-1,3-diol Chemical compound CC(O)C(C)C1=CC(O)=CC(O)=C1C ZYUVGYBAPZYKSA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UGPPSZLVMYZGDE-UHFFFAOYSA-N CCNC(N(CCc1c2)C(c3c(C)cc(C)cc3)c1cc(OCCc1nccnc1)c2OC)=O Chemical compound CCNC(N(CCc1c2)C(c3c(C)cc(C)cc3)c1cc(OCCc1nccnc1)c2OC)=O UGPPSZLVMYZGDE-UHFFFAOYSA-N 0.000 description 2
- WIEJUSZIJJORLO-UHFFFAOYSA-N Cl.CC1=C(C=CC(=C1)C)C1N(CCC2=CC(=C(C=C12)OCCC=1C=NC=CC=1)C(=O)O)C(NCC=1N=COC=1)=O Chemical compound Cl.CC1=C(C=CC(=C1)C)C1N(CCC2=CC(=C(C=C12)OCCC=1C=NC=CC=1)C(=O)O)C(NCC=1N=COC=1)=O WIEJUSZIJJORLO-UHFFFAOYSA-N 0.000 description 2
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a novel class of tetrahydroisoquinoline compounds and to compositions comprising the same.
- the compounds and compositions (such as pharmaceutical compositions) of the present invention can be used as medicaments in the treatment of cancer.
- RAS When RAS is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation and survival. Mutations in ras genes can lead to the production of permanently activated RAS proteins. As a result, this can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals.
- RAS genes HRas, KRas, and NRas are the most common oncogenes in human cancer; mutations that permanently activate RAS are found in 20% to 25% of all human tumors and up to 90% in certain types of cancer.
- KRAS is the most frequently mutated RAS isoform having been shown to be mutated in 90% of pancreatic adenocarcinoma, 45% of colon rectal cancers and 35% of lung adenocarcinoma. KRAS mutations have been associated with increased tumorigenicity and poor prognosis.
- Cisplatin is used to treat various types of cancers, including sarcomas, some carcinomas (e.g., small cell lung cancer, squamous cell carcinoma of the head and neck and ovarian cancer), lymphomas, bladder cancer, cervical cancer and germ cell tumors. Even though it resulted to be very effective in some kinds of cancer (such as testicular cancer) it shows a number of side-effects that can limit its use. Furthermore, according to the mechanism of action proposed for cisplatin, it should interfere with DNA replication, killing the fastest proliferating cells, which in theory are carcinogenic. However, cisplatin is not really selective towards carcinogenic cells.
- Patent application WO 2016/033105 A1 discloses capsazepine derivatives, their use in pharmaceutical compositions and methods of using the compounds for treating diseases such as cancer.
- Table 1 of WO 2016/033105 A1 shows the structures of some of the compounds disclosed therein.
- the present invention provides a novel class of compounds having Formula I and/or Formula II, which includes enantiomers and pharmaceutically acceptable salts thereof.
- the compounds of the present invention selectively and effectively inhibit RAS proteins, and particularly KRAS proteins, thereby representing excellent anti-cancer drugs useful in the treatment of a variety of cancers, such as large intestine cancer, colon cancer, rectal cancer, pancreatic cancer, breast cancer, multiple myeloma, leukemia and lung cancer.
- the compounds of the present invention also exhibit lower toxicity.
- the compounds of the present invention are compounds of Formula I, enantiomers or pharmaceutically acceptable salts thereof: wherein
- C 1-4 alkyl is intended to mean a linear or branched hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl,n-propyl,isopropyl,n-butyl,iso-butyl, sec-butyl,and tert-butyl.
- C 2-4 alkenyl is intended to cover linear or branched hydrocarbon groups having 2 to 4 carbon atoms and comprising a double bond.
- alkenyl groups are vinyl, allyl, and butenyl.
- Preferred examples of alkenyl are vinyl and allyl, especially allyl.
- C 2-4 alkynyl is intended to mean a linear or branched hydrocarbon group having 2 to 4 carbon atoms and containing a triple bond.
- Illustrative examples of C 2-4 alkynyl groups include acetylene, propynyl, butynyl, as well as branched forms of these.
- the position of unsaturation may be at any position along the carbon chain. More than one bond may be unsaturated such that the "C 2-4 alkynyl” is a di-yne as is known to the person skilled in the art.
- C 1-4 alkanediyl is intended to mean a divalent linear or branched hydrocarbon group having 1 to 4 carbon atoms, such as methanediyl, ethanediyl,propanediyl, or butanediyl.
- C 2-4 alkenediyl is intended to cover divalent linear or branched hydrocarbon groups having 2 to 4 carbon atoms and comprising a double bond.
- C 2-4 alkynediyl is intended to mean a divalent linear or branched hydrocarbon group having 2 to 4 carbon atoms and containing a triple bond.
- halogen includes fluoro, chloro, bromo, and iodo, more particularly, fluoro, chloro and bromo.
- aromatic ring or ring system is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl.
- heteroaromatic ring or ring system groups examples include oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl and phenoxazonyl.
- heterocyclic groups examples include imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydrothi
- the term “optionally substituted” is intended to mean that the group in question may be substituted at least once. Furthermore, the term “optionally substituted” may also mean that the group in question is unsubstituted.
- the compounds of the present invention can be in a free form or in the form of a pharmaceutically acceptable salt.
- pharmaceutically acceptable salt is to be understood as a salt formed with either a base or an acid, wherein the resulting counter-ion does not significantly add to the toxicity of the compound of the present invention.
- Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, etc., organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or maleate, etc. Also, when the compound has a substituent such as carboxyl group, there may be mentioned a salt with a base (for example, alkali metal salt such as sodium salt, potassium salt, etc. or alkaline earth metal salt such as calcium salt, etc.).
- a base for example, alkali metal salt such as sodium salt, potassium salt, etc. or alkaline earth metal salt such as calcium salt, etc.
- the compounds of the invention are compounds of Formula I, enantiomers or pharmaceutically acceptable salts thereof: wherein
- R 8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, C 1-4 alkyl, OC 1-4 alkyl, CO 2 -C 1-4 alkyl, halogen, CONH 2 , CN, and COOH.
- R 8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, OCH 3 , CO 2 CH 3 , halogen, CONH 2 , CN, and COOH.
- R 8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, OCH 3 , CO 2 CH 3 , F, CONH 2 , CN, and COOH.
- R 8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, OCH 3 , and F.
- R 8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH and F.
- R 8a is a phenyl ring, optionally substituted with at least 1 OH group.
- At least one substituent is in the meta position relative to the position connecting the phenyl ring to the tetrahydroisoquinoline core.
- R 8a may also be a 5 or 6-membered heteroaromatic ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, C 1-4 alkyl, OC 1-4 alkyl, CO 2 -C 1-4 alkyl, halogen, CONH 2 , CN, and COOH, such as OH, OCH 3 , CO 2 CH 3 , halogen, CONH 2 , CN, and COOH, particularly OH, OCH 3 , CO 2 CH 3 , F, CONH 2 , CN, and COOH, more particularly, OH, OCH 3 , and F, even more particularly OH and F, such as OH.
- substituent selected from the group consisting of OH, C 1-4 alkyl, OC 1-4 alkyl, CO 2 -C 1-4 alkyl, halogen, CONH 2 , CN, and COOH, such as OH, OCH 3 , CO 2 CH 3 , halogen, CONH 2 , CN
- R 8a is optionally substituted pyridinyl, indanyl, dihydro-benzofuranyl, indolinyl or triazolopyrimidinyl. In a further embodiment, R 8a is optionally substituted pyridinyl, optionally substituted indanyl, or optionally substituted dihydro-benzofuranyl. In another embodiment, R 8a is optionally substituted indanyl or optionally substituted pyridinyl. In yet another embodiment, R 8a is pyridinyl.
- R 3 is -(CH 2 ) n 3 -C(Y 3 )-(X 3 ) m 3 -(CH 2 ) k 3 -R 3a .
- Y 3 is O.
- X 3 is NH.
- Y 3 is O and X 3 is NH.
- n 3 is 0.
- m 3 is 1.
- n 3 is 0 and m 3 is 1.
- R 3a is oxazolyl or pyridinyl, such as oxazol-4-yl or pyridin-4-yl.
- k 3 is 1.
- R 1 is (R y ) k 1 -(Y 1 ) n 1 -(X 1 ) m 1 -R x , (R y ) k 1 -(X 1 ) m 1 -(Y 1 ) n 1 -R x or halogen.
- R 1 is OR x or Y 1 X 1 R x .
- R 1 is OR x .
- R 1 is OCH 3 .
- R 2 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, OC 1-4 alkyl, OC 2-4 alkenyl, or OC 2-4 alkynyl,. In one embodiment, R 2 is H or O-C 1-4 alkyl. In another embodiment, R 2 is H.
- R 4 is halogen, OC 1-4 alkyl, OC 2-4 alkenyl, OC 2-4 alkynyl, C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl. In one embodiment, R 4 is halogen or C 1-2 alkyl. In a further embodiment, R 4 is Cl, F, or C 1-2 alkyl. In still a further embodiment, R 4 is Cl, F, or CH 3 . In another embodiment, R 4 is Cl or CH 3 . In yet another embodiment, R 4 is CH 3 .
- R 5 is hydrogen, OC 1-4 alkyl, OC 2-4 alkenyl, OC 2-4 alkynyl, OH, C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, each C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl independently optionally substituted with 1 to 3 halogens, such as F.
- R 5 is H, C 1-2 alkyl, or OC 1-2 alkyl.
- R 5 is C 1-2 alkyl or OC 1-2 alkyl.
- R 5 is CH 3 or OCH 3 .
- R 5 is CH 3 .
- R 6 is H, OH, halogen, or NH 2 . In one embodiment, R 6 is H or OH. In a further embodiment, R 6 is H.
- R 7 is H, halogen, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OC 1-4 alkyl, OC 2-4 alkenyl, or OC 2-4 alkynyl. In one embodiment, R 7 is H, CH 3 , or OCH 3 . In a further embodiment, R 7 is H or OCH 3 . In another embodiment, R 7 is H.
- the compounds of the invention are compounds of Formula II, enantiomers or pharmaceutically acceptable salts thereof: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above, and wherein the phenyl ring is substituted with R 8b at least once, each R 8b independently selected from the group consisting of OH, C 1-4 alkyl, OC 1-4 alkyl, CO 2 -C 1-4 alkyl, halogen, CONH 2 , CN, and COOH.
- each R 8b is independently selected from the group consisting of OH, OCH 3 , CO 2 CH 3 , halogen, CONH 2 , CN, and COOH.
- each R 8b is independently selected from the group consisting of OH, OCH 3 , CO 2 CH 3 , F, CONH 2 , CN, and COOH.
- each R 8b is independently selected from the group consisting of OH, OCH 3 , and F.
- each R 8b is independently selected from the group consisting of OH and F.
- R 8b is an OH group.
- at least one R 8b substituent is in the meta position relative to the ethyl-oxy group to which the phenyl group is bound.
- the compounds of the invention are compounds of Formula IIa, enantiomers or pharmaceutically acceptable salts thereof: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above, and wherein R 8c is an additional optionally substituted cyclic, heterocyclic, aromatic, or heteroaromatic ring. In one embodiment, R 8c is an optionally substituted cyclic, heterocyclic, or heteroaromatic ring.
- the compounds of the invention are compounds of Formula III, enantiomers or pharmaceutically acceptable salts thereof: wherein R 1 , R 3 , R 4 , R 5 , and R 8b are as defined above.
- at least one R 8b substituent is in the meta position relative to the ethyl-oxy group to which the phenyl group is bound.
- the compound of the invention is selected from the group consisting of compounds 1-63, enantiomers, and pharmaceutically acceptable salts thereof: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63
- the compounds of the present invention are intended for use as a medicament.
- the compounds of the invention may in principle be applied on their own, but they are preferably formulated with a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier is an inert carrier suitable for each administration method, and can be formulated into conventional pharmaceutical preparation (tablets, granules, capsules, powder, solution, suspension, emulsion, injection, infusion, etc.).
- a carrier there may be mentioned, for example, a binder, an excipient, a lubricant, a disintegrant and the like, which are pharmaceutically acceptable.
- they When they are used as an injection solution or an infusion solution, they can be formulated by using distilled water for injection, physiological saline, an aqueous glucose solution.
- the administration method of the compounds of the present invention is not particularly limited, and a usual oral or parenteral administration method (intravenous, intramuscular, subcutaneous, percutaneous, intranasal, transmucosal, enteral, etc.) can be applied.
- a usual oral or parenteral administration method intravenous, intramuscular, subcutaneous, percutaneous, intranasal, transmucosal, enteral, etc.
- the dosage of the tetrahydroisoquinoline derivatives or a pharmaceutically acceptable salts thereof of the present invention may optionally be set in a range of an effective amount sufficient for showing a pharmacological effect, in accordance with the potency or characteristics of the compound to be used as an effective ingredient.
- the dosage may vary depending on administration method, age, body weight or conditions of a patient.
- the invention concerns a compound or composition according to the invention for use in the treatment of cancer.
- cancer In particular Ras-driven cancer, Ras genes being the first oncogenes identified in human cancer cells.
- the invention concerns a compound or composition according to the invention for use in the treatment of leukemias, lymphomas, myelomas, colorectal cancer, pancreatic cancer, breast cancer and lung cancer, among other types of cancer.
- the substituted tetrahydroisoquinolines L of the present invention are generally prepared in eight steps as outlined in Scheme 1.
- ether D is prepared from phenol A by means of a Mitsunobu reaction (reagent B) [ G. Liu. et al., Journal of Medicinal Chemistry 2007, 50, 3086-3100 ] or a nucleophilic substitution reaction (reagent C) under suitable conditions well known in the art.
- R 9 is the protected version of R 8 in case R 8 contains substituents in need of protection during steps 2, 3, and/or 4.
- R 9 could be a benzyloxy-protected R 8 , where R 8 contains a free OH substituent.
- step 4 the substitution reaction of compound F using sodium cyanide as the nucleophile provides nitrile G which is reduced to amine H using H 2 and 10% Pd/C as the catalyst (step 5). Hydrogenation of nitrile G additionally involves phenol de-protection of those compounds bearing a protecting group in R 9 (Scheme 1b) of an OH group in R 8 . Since hydrochloric acid is used as an additive in the reaction, the amine H is obtained as the hydrochloride salt. Steps 6-7 involve a well-known Pictet-Spengler reaction [ A. Yokohama et al., Journal of Organic Chemistry 1999, 64, 611-617 ; R.
- phenol A is protected using a suitable phenol protecting group PG 8 , where PG 8 may be a benzyl group.
- PG 8 may be a benzyl group.
- Reduction of aldehyde B with sodium borohydride in methanol (step 2) leads to alcohol C which is then converted to alkyl chloride D using thionyl chloride (step 3).
- the substitution reaction of compound D using sodium cyanide as the nucleophile provides nitrile E which is reduced to amine F using H 2 and 10% Pd/C as the catalyst (step 5). Since hydrochloric acid is used as an additive in the reaction, the amine F is obtained as a hydrochloride salt. Hydrogenation of nitrile E additionally involves phenol de-protection.
- Steps 6-7 involve a well-known Pictet-Spengler reaction [ A. Yokohama et al., Journal of Organic Chemistry 1999, 64, 611-617 ; R. Gitto et al., Journal of Medicinal Chemistry 2003, 46, 197-200 ] where arylethylamines F are condensed with different substituted benzaldehydes G to give the corresponding imines H which upon treatment with refluxing trifluoroacetic acid undergo intramolecular cyclization to afford tetrahydroisoquinolines I as racemic mixtures.
- the Bischler-Napieralski reaction [ J. E. De Los Angeles. Journal of Medicinal Chemistry 1996, 39, 3701-3711 ; G.
- amine I is protected using a suitable protecting group PG 3 , where PG 3 may be a Boc protecting group.
- Phenol alkylation is carried out in step 9 by means of a Mitsunobu reaction (reagent K) [ G. Liu. et al., Journal of Medicinal Chemistry 2007, 50, 3086-3100 ] or a nucleophilic substitution (reagent L) under suitable conditions well known in the art.
- the amine group of formula M is de-protected under acidic conditions to provide amine N as a hydrochloride salt.
- the R 3 substituent is introduced by means of different synthetic strategies well known in the art.
- R 8 -OH is one of the building blocks shown in Table 1, they may be prepared according to Scheme 3 below: 1 2 3 Table 1
- step 1 2-(3-bromophenyl)ethanol A is converted to 3-(2-hydroxyethyl)benzonitrile 1 using copper cyanide [referring to the method disclosed in WO 00/78708 A1 , Example 23, pages 28-29].
- Compound 1 is then subjected to basic hydrolysis (step 2a) to prepare benzoic acid 2 or to acid hydrolysis (step 2b) to synthesize benzamide 3 [referring to WO 20091055077A1 , page 384, REAGENT PREPARATION 14].
- step 1 compound A is subjected to electrophilic aromatic substitution by means of different synthetic strategies well known in the art.
- step 2 amine B reacts with acid C under suitable coupling conditions to give amide D.
- Steps 3-4 involve a well-known Bischler-Napieralski reaction [ J. E. De Los Angeles. Journal of Medicinal Chemistry 1996, 39, 3701-3711 ; G. Fodor et al., Angewandte Chemie Int. Ed. 1972, 11, 919-920 ] which is used to synthesize tetrahydroisoquinolines F lacking an electron-donating group in the R 10 or R 2 position.
- step 7 the amine group of formula H is de-protected under acidic conditions to provide amine I as a hydrochloride salt.
- step 8 the R 3 substituent is introduced by means of different synthetic strategies well known in the art.
- Step 9 involves reaction of compound J with BBr 3 at low temperature to afford compound K [ WO 2011/017125 , page 110, step 3].
- Phenol alkylation is carried out in step 10 by means of a Mitsunobu reaction (reagent L) [ G. Liu. et al., Journal of Medicinal Chemistry 2007, 50, 3086-3100 ] or a nucleophilic substitution (reagent M) under suitable conditions well known in the art.
- step 11 the substituent R 11 is converted to the corresponding substituent R 1 by means of different synthetic strategies well described in the prior art, which may require different steps depending on the nature of the substituent R 1 .
- Hydrogenation of compound O (scheme 4b) involves phenol de-protection of those compounds bearing a protecting group in R 9 .
- R 3 is C(O)NHR 3a , i.e. when n 3 is 0, Y 3 is O, X 3 is NH, m 3 is 1, and k 3 is 0, amine K (Scheme 1) or amine N (Scheme 2) are coupled with R 3a NH 2 using 1,1-carbonyldiimidazole as coupling agent and a suitable base (e.g. triethylamine) to afford the corresponding ureas L and O respectively [ WO 2015/089337 ] .
- a suitable base e.g. triethylamine
- Step 7 Synthesis of 3-(2-((1-(2,4-dimethylphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)ethyl)phenol 2,2,2-trifluoroacetate
- Step 7A 3-(2-(4-(2-((2,4-dimethylbenzylidene)amino)ethyl)-2-methoxyphenoxy)ethyl)phenol
- Step 7B 3-(2-((1-(2,4-dimethylphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)ethyl)phenol 2,2,2-trifluoroacetate
- Step 8 Synthesis of 1-(2,4-dimethylphenyl)-7-(3-hydroxyphenethoxy)-6-methoxy-N-(oxazol-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
- compounds 3, 5-13, 16, 17, 19-22, 25, 26, 29, and 46-53 may also be prepared according to schemes 1 or 1b.
- Compounds 1, 2, 4, 14, 15, 23 and 54-63 may be prepared according to scheme 2.
- Compounds 27, 30 and 31 may be prepared according to schemes 2 and 3.
- Step 5 Synthesis of tert-butyl 6-bromo-1-(2,4-dimethylphenyl)-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate
- Step 7 Synthesis of methyl 1-(2,4-dimethylphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride
- Step 8 Synthesis of methyl 1-(2,4-dimethylphenyl)-7-methoxy-2-((oxazol-4-ylmethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
- reaction was stirred at room temperature. After 4h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water 0-100% gradient) to give the title product as a white solid (189 mg, 60% yield).
- Step 9 Synthesis of methyl 1-(2,4-dimethylphenyl)-7-hydroxy-2-((oxazol-4-ylmethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
- Step 10 Synthesis of methyl 1-(2,4-dimethylphenyl)-2-((oxazol-4-ylmethyl)carbamoyl)-7-(2-(pyridin-3-yl)ethoxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
- Step 11 Synthesis of 1-(2,4-dimethylphenyl)-2-((oxazol-4-ylmethyl)carbamoyl)-7-(2-(pyridin-3-yl)ethoxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride
- Step 12 Synthesis of 1-(2,4-dimethylphenyl)-N2-(oxazol-4-ylmethyl)-7-(2-(pyridin-3-yl)ethoxy)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide
- compounds 24, 28, 32, 33 and 35-45 may also be prepared according to schemes 4 or 4b.
- Example 3 activity in tumor cell lines
- Cell lines were cultured in DMEM or RPMI-1640 supplemented with FBS 10%.
- cells were seeded at a density of 1.8x10 3 , 6.2 x10 3 , 7.8 x10 3 , 21 x10 3 and 2x10 3 cells/cm 2 , respectively, in tissue culture microplates and were incubated in humidified atmosphere at 5% CO 2 .
- compounds dissolved in DMSO 100% were added for different final concentrations ranging between 0.1 and 50 ⁇ M for a final DMSO concentration of 0.5% and the plates were incubated for another 72 h.
- IC50 values cell proliferation inhibition Compound A549 RPMI-8226 H358 PANC-1 1 11.73 2.17 18.31 17.26 2 8.25 1.8 12.12 17.29 3 1.97 1.21 1.66 1.59 4 10.09 2.67 >20 29.67 5 4.82 1.51 >20 >30 6 9.09 5.65 19.94 24.72 7 6.34 2.41 18.1 24.77 8 4.11 2.11 11.22 11.11 9 3.65 0.74 18.95 24.50 10 15.87 0.86 19.76 15.03 11 18.03 1.47 8.52 12.27 12 8.99 4.98 16.82 13.59 13 9.37 2.86 15.75 12.59 14 >10 3.94 >10 >30 15 2.14 0.89 2.58 2.13 16 >5 0.48 7.24 11.97 17 3.52 1.74 3.10 1.83 18 1.97 1.21 1.66 1.59 19 0.95 2.93 0.68 0.57 20 0.75 0.60 0.48 0.56 21 1.33 0.90 0.78 0.81 22 0.89 0.82 0.65 0.60 23 0.55 0.62 0.59 0.49 24 0.74 0.87 0.84 0.66 25 0.55 0.58 0.
- Data shown for compounds 1-53 are the median from experimental results. Data shown for compounds 54-63 are based on estimations and/or preliminary experimental results.
- the results of the body weight changes in the tumor bearing mice are shown in Figure 1 .
- the body weight loss (BWL) of just one mouse reached 10% in group 2 (compound 18, 10 mg/kg), while the BWL of 4 mice in group 3 (Cisplatin, 3.5 mg/kg) reached 10% or even lower.
- the tumor growth curves of the different groups are shown in Figure 2 .
- the mean tumor volume of group-1 (vehicle) reached 630mm 3 on Day 24 after inoculation (PG-D22, Day 22 after first-dosing).
- the mean tumor volume of group-2 (Compound 18, 10 mg/kg) reached 238mm 3 on PG-D22, and TGI is about 62%.
- the mean tumor volume of group-3 (Cisplatin, 3.5mg/kg) reached 231mm 3 on PG-D22, and TGI is about 63%.
- test compound 18 demonstrated significant anti-tumor activities in subcutaneous NCI-H358 human lung cancer xenograft model, and 10mg/kg b.i.d. of compound 18 is safe for the bearing mice.
- the protocol to determine KD is as follows:
- the chip was then blocked with 5% (w/v) non-fat milk in water overnight, and washed with 10 ⁇ PBST for 10 min, 1 ⁇ PBST for 10 min, and deionized water twice for 10 min before being dried under a stream of nitrogen prior to use.
- SPRi measurements were performed with PlexAray HT (Plexera Bioscience, Seattle, WA, US). Collimated light (660 nm) passes through the coupling prism, reflects off the SPR-active gold surface, and is received by the CCD camera. Buffers and samples were injected by a non-pulsatile piston pump into the 30 ⁇ L flowcell that was mounted on the coupling prim.
- Each measurement cycle contained four steps: washing with PBST running buffer at a constant rate of 2 ⁇ L/s to obtain a stable baseline, Compound 18 injection at 5 uL/s for binding, surface washing with PBST at 2 ⁇ L/s for 300 s, and regeneration with 0.5% (v/v) H3PO4 at 2 ⁇ L/s for 300 s. All measurements were performed at 4°C. The signal changes after binding and washing (in AU) are recorded as the assay value. Selected protein-grafted regions in the SPR images were analyzed, and the average reflectivity variations of the chosen areas were plotted as a function of time. Real-time binding signals were recorded and analyzed by Data Analysis Module (DAM, Plexera Bioscience, Seattle, WA, US). Kinetic analysis was performed using BIAevaluation 4.1 software (Biacore, Inc.).
- Example 6 Efficacy testing in 3D viability assay for NIH-H358 cell line
- the protocol to perform 3D CellTiter-GloTM cell viability assay is as follows:
Description
- The present invention relates to a novel class of tetrahydroisoquinoline compounds and to compositions comprising the same. The compounds and compositions (such as pharmaceutical compositions) of the present invention can be used as medicaments in the treatment of cancer.
- Cancer genome sequencing efforts over the past 10 to 15 years have led to the identification of numerous oncogenes responsible for the development and maintenance of human cancer. Despite the identification of more than 500 validated cancer genes the three RAS genes HRAS, NRAS and KRAS still constitute the most frequently mutated oncogene family in human cancer.
- When RAS is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation and survival. Mutations in ras genes can lead to the production of permanently activated RAS proteins. As a result, this can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals.
- Because these signals result in cell growth and division, overactive RAS signaling can ultimately lead to cancer. The 3 RAS genes (HRas, KRas, and NRas) are the most common oncogenes in human cancer; mutations that permanently activate RAS are found in 20% to 25% of all human tumors and up to 90% in certain types of cancer.
- Cancers harboring RAS mutations remained essentially untreatable more than 30 years after the initial discovery of the oncogene. Thus, for many years RAS was considered to be "undruggable".
- Among HRAS, NRAS and KRAS, KRAS is the most frequently mutated RAS isoform having been shown to be mutated in 90% of pancreatic adenocarcinoma, 45% of colon rectal cancers and 35% of lung adenocarcinoma. KRAS mutations have been associated with increased tumorigenicity and poor prognosis.
- To date, different types of drugs are used as anticancer drugs and cisplatin represents one of the most popular. Cisplatin is used to treat various types of cancers, including sarcomas, some carcinomas (e.g., small cell lung cancer, squamous cell carcinoma of the head and neck and ovarian cancer), lymphomas, bladder cancer, cervical cancer and germ cell tumors. Even though it resulted to be very effective in some kinds of cancer (such as testicular cancer) it shows a number of side-effects that can limit its use. Furthermore, according to the mechanism of action proposed for cisplatin, it should interfere with DNA replication, killing the fastest proliferating cells, which in theory are carcinogenic. However, cisplatin is not really selective towards carcinogenic cells.
- Patent application
WO 2016/033105 A1 discloses capsazepine derivatives, their use in pharmaceutical compositions and methods of using the compounds for treating diseases such as cancer. Table 1 ofWO 2016/033105 A1 shows the structures of some of the compounds disclosed therein. - Marín-Ramos et al. ("Blocking Ras inhibition as an antitumor strategy", Seminars in Cancer Biology, 2018-02-01) is a review article disclosing several small molecules that are inhibitors of RAS. However, none of these compounds have a tetrahydroisoquinoline structure.
- Chun Xie et al. ("Identification of a New Potent Inhibitor Targeting KRAS in Non-small Cell Lung Cancer Cells", Frontiers in Pharmacology, vol. 8, 14 November 2017) describes a study in which a small molecule inhibitor compound 0375-0604 targeting KRAS was identified. This compound, having a benzothiazole ring moiety was found to inhibit KRAS.
- Thus, there is still a need to provide novel compounds acting as anti-cancer drugs and, at the same time, having low toxicity.
- The present invention provides a novel class of compounds having Formula I and/or Formula II, which includes enantiomers and pharmaceutically acceptable salts thereof. The compounds of the present invention selectively and effectively inhibit RAS proteins, and particularly KRAS proteins, thereby representing excellent anti-cancer drugs useful in the treatment of a variety of cancers, such as large intestine cancer, colon cancer, rectal cancer, pancreatic cancer, breast cancer, multiple myeloma, leukemia and lung cancer. Compared to known compounds used in the treatment of cancer, the compounds of the present invention also exhibit lower toxicity.
-
- R1 is (Ry)k 1-(Y1)n 1-(X1)m 1-Rx, (Ry)k 1-(X1)m 1-(Y1)n 1-Rx or halogen such as ORx or Y1X1Rx, more particularly ORx,
- Y1 is C(O) or S(O)2, such as C(O),
- X1 is NH or O,
- Ry is C1-4 alkanediyl, C2-4alkenediyl, or C2-4 alkynediyl, such as -CH2-,
- Rx is C1-4 alkyl, C2-4alkenyl, C2-4alkynyl, or H, such as CH3 or H;
- k1 is 0 or 1,
- n1 is 0 or 1,
- m1 is 0 or 1,
- R2 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl, such as H, CH3, or OCH3, particularly H or OCH3, more particularly H;
- R3 is -(CH2)n 3-C(Y3)-(X3)m 3-(CH2)k 3-R3a,
- n3 is an integer in the range of 0 to 2, such as 0 or 2,
- X3 is S, NH, or O, such as NH or O, particularly NH,
- Y3 is S or O, such as O,
- m3 is 0 or 1,
- k3 is 0 or 1,
- R3a is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, Het3, Ar3, HetCyc3 or Cyc3, such as C1-4 alkyl or Het3,
- Het3 is a 5- to 10-membered heteroaromatic ring or ring system containing one or more heteroatoms selected from the group consisting of N, O, and S, such as oxazolyl, thiazolyl, or pyridinyl, particularly oxazol-4-yl, thiazol-4-yl, or pyridin-4-yl,
- Ar3 is a 6- to 10-membered aromatic ring or ring system, such as phenyl or naphtyl, HetCyc3 is a 3- to 8-membered heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, such as pyrrolidinyl, oxazolidinyl, morpholinyl,
- Cyc3 is a 3- to 8-membered cyclyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
- R4 is halogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl, such as halogen or C1-2 alkyl, particularly Cl, F, or C1-2 alkyl, more particularly, Cl, F, or CH3, even more particularly Cl or CH3, such as CH3;
- R5 is hydrogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, OH, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl, each C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl independently optionally substituted with 1 to 3 halogens, such as F, , particularly H, C1-2 alkyl, or OC1-2 alkyl, more particularly C1-2 alkyl or OC1-2 alkyl, even more particularly CH3 or OCH3, such as CH3;
- R6 is H, OH, halogen, or NH2, such as H or OH, more particularly H;
- R7 is H, halogen, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl, such as H, CH3, or OCH3, particularly H or OCH3, more particularly H;
- R8 is -(CH2)n 8-(C(O))m 8-R8a,
- n8 is an integer from 1 to 2, such as 2,
- m8 is an integer from 0 to 1, such as 0, and
- R8a is an aromatic or heteroaromatic ring having 5 or 6 ring members, optionally substituted with at least 1 substituent selected from the group consisting of OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, CO2-C1-4 alkyl, CO2-C2-4 alkenyl, CO2-C2-4 alkynyl, halogen, CONH2, CN, COOH, -OCO-C1-4 alkyl, -OCO-C2-4 alkenyl, -OCO-C2-4 alkynyl, -NHCO-C1-4 alkyl, -NHCO-C2-4 alkenyl, -NHCO-C2-4 alkynyl, NH2, NHC1-4 alkyl, NHC2-4 alkenyl, NHC2-4 alkynyl, N(C1-4 alkyl)2, N(C2-4 alkenyl)2, N(C2-4 alkynyl)2, CONHC1-4 alkyl, CONHC2-4 alkenyl, CONHC2-4 alkynyl, CON(C1-4 alkyl)2, CON(C2-4 alkenyl)2, CON(C2-4 alkynyl)2, such as OH, OCH3, CO2CH3, halogen, CONH2, CN, and COOH, particularly OH, OCH3, CO2CH3, F, CONH2, CN, and COOH, more particularly, OH, OCH3, and F, even more particularly OH and F, such as OH; or R8a is an aromatic or heteroaromatic ring having 5 or 6 ring members fused with an additional optionally substituted cyclic, heterocyclic, aromatic, or heteroaromatic ring, such as an optionally substituted cyclic, heterocyclic, or heteroaromatic ring.
- In the present context, the term "C1-4 alkyl" is intended to mean a linear or branched hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl,n-propyl,isopropyl,n-butyl,iso-butyl, sec-butyl,and tert-butyl.
- Similarly, the term "C2-4 alkenyl" is intended to cover linear or branched hydrocarbon groups having 2 to 4 carbon atoms and comprising a double bond. Examples of alkenyl groups are vinyl, allyl, and butenyl. Preferred examples of alkenyl are vinyl and allyl, especially allyl.
- In the present context the term "C2-4 alkynyl" is intended to mean a linear or branched hydrocarbon group having 2 to 4 carbon atoms and containing a triple bond. Illustrative examples of C2-4 alkynyl groups include acetylene, propynyl, butynyl, as well as branched forms of these. The position of unsaturation (the triple bond) may be at any position along the carbon chain. More than one bond may be unsaturated such that the "C2-4 alkynyl" is a di-yne as is known to the person skilled in the art.
- In the present context, the term "C1-4 alkanediyl" is intended to mean a divalent linear or branched hydrocarbon group having 1 to 4 carbon atoms, such as methanediyl, ethanediyl,propanediyl, or butanediyl.
- Similarly, the term "C2-4 alkenediyl" is intended to cover divalent linear or branched hydrocarbon groups having 2 to 4 carbon atoms and comprising a double bond.
- In the present context the term "C2-4 alkynediyl" is intended to mean a divalent linear or branched hydrocarbon group having 2 to 4 carbon atoms and containing a triple bond.
- Herein, the term "halogen" includes fluoro, chloro, bromo, and iodo, more particularly, fluoro, chloro and bromo.
- In the present context the term "aromatic ring or ring system" is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl.
- The term "heteroaromatic ring or ring system" is intended to mean a fully or partially aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen (=N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heteroaromatic ring or ring system groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl and phenoxazonyl.
- In the present context, the term "heterocyclic ring or ring system" is intended to mean a non-aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen (=N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heterocyclic groups are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydrothiopyrane, thiepane, dithiane, dithiepane, dioxane, dioxepane, oxathiane and oxathiepane.
- In the present context, the term "optionally substituted" is intended to mean that the group in question may be substituted at least once. Furthermore, the term "optionally substituted" may also mean that the group in question is unsubstituted.
- The compounds of the present invention can be in a free form or in the form of a pharmaceutically acceptable salt. In the context of the present invention, the term "pharmaceutically acceptable salt" is to be understood as a salt formed with either a base or an acid, wherein the resulting counter-ion does not significantly add to the toxicity of the compound of the present invention.
- Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, etc., organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or maleate, etc. Also, when the compound has a substituent such as carboxyl group, there may be mentioned a salt with a base (for example, alkali metal salt such as sodium salt, potassium salt, etc. or alkaline earth metal salt such as calcium salt, etc.).
-
- R1 is (Ry)k 1-(Y1)n 1-(X1)m 1-Rx, (Ry)k 1-(X1)m 1-(Y1)n 1-Rx or halogen such as ORx or Y1X1Rx, more particularly ORx,
- Y1 is C(O) or S(O)2, such as C(O),
- X1 is NH or O,
- Ry is C1-4 alkanediyl, C2-4alkenediyl, or C2-4 alkynediyl, such as -CH2-,
- Rx is C1-4 alkyl, C2-4alkenyl, C2-4alkynyl, or H, such as CH3 or H;
- k1 is 0 or 1,
- n1 is 0 or 1,
- m1 is 0 or 1,
- R2 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl, such as H, CH3, or OCH3, particularly H or OCH3, more particularly H;
- R3 is -(CH2)n 3-C(Y3)-(X3)m 3-(CH2)k 3-R3a,
- n3 is an integer in the range of 0 to 2, such as 0 or 2,
- Y3 is S or O, such as O,
- X3 is S, NH, or O, such as NH or O, particularly NH,
- m3 is 0 or 1,
- k3 is 0 or 1,
- R3a is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, Het3, Ar3, HetCyc3 or Cyc3, such as C1-4 alkyl or Het3,
- Het3 is a 5- to 10-membered heteroaromatic ring or ring system containing one or more heteroatoms selected from the group consisting of N, O, and S, such as oxazolyl, thiazolyl, or pyridinyl, particularly oxazol-4-yl, thiazol-4-yl, or pyridin-4-yl,
- Ar3 is a 6- to 10-membered aromatic ring or ring system, such as phenyl or naphtyl, HetCyc3 is a 3- to 8-membered heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, such as pyrrolidinyl, oxazolidinyl, morpholinyl,
- Cyc3 is a 3- to 8-membered cyclyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
- R4 is halogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl, such as halogen or C1-2 alkyl, particularly Cl, F or C1-2 alkyl, more particularly, Cl, F, or CH3, even more particularly Cl or CH3, such as CH3;
- R5 is hydrogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, OH, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl, each C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl independently optionally substituted with 1 to 3 halogens, such as F, , particularly H, C1-2 alkyl, or OC1-2 alkyl, more particularly C1-2 alkyl or OC1-2 alkyl, even more particularly CH3 or OCH3, such as CH3;
- R6 is H, OH, halogen, or NH2, such as H or OH, more particularly H;
- R7 is H, halogen, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl, such as H, CH3, or OCH3, particularly H or OCH3, more particularly H;
- R8 is -(CH2)n 8-(C(O))m 8-R8a,n8 is an integer from 1 to 2, such as 2
- m8 is an integer from 0 to 1, such as 0, and
- R8a is an aromatic or heteroaromatic ring having 5 or 6 ring members, optionally substituted with at least 1 substituent selected from the group consisting of OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, CO2-C1-4 alkyl, CO2-C2-4 alkenyl, CO2-C2-4 alkynyl, halogen, CONH2, CN, COOH, -OCO-C1-4 alkyl, -OCO-C2-4 alkenyl, -OCO-C2-4 alkynyl, -NHCO-C1-4 alkyl, -NHCO-C2-4 alkenyl, -NHCO-C2-4 alkynyl, NH2, NHC1-4 alkyl, NHC2-4 alkenyl, NHC2-4 alkynyl, N(C1-4 alkyl)2, N(C2-4 alkenyl)2, N(C2-4 alkynyl)2, CONHC1-4 alkyl, CONHC2-4 alkenyl, CONHC2-4 alkynyl, CON(C1-4 alkyl)2, CON(C2-4 alkenyl)2, CON(C2-4 alkynyl)2, such as OH, OCH3, CO2CH3, halogen, CONH2, CN, and COOH, particularly OH, OCH3, CO2CH3, F, CONH2, CN, and COOH, more particularly, OH, OCH3, and F, even more particularly OH and F, such as OH; or R8a is an aromatic or heteroaromatic ring having 5 or 6 ring members fused with an additional optionally substituted cyclic, heterocyclic, aromatic, or heteroaromatic ring, such as an optionally substituted cyclic, heterocyclic, or heteroaromatic ring.
- In one embodiment, R8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, C1-4 alkyl, OC1-4 alkyl, CO2-C1-4 alkyl, halogen, CONH2, CN, and COOH. In another embodiment, R8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, OCH3, CO2CH3, halogen, CONH2, CN, and COOH. In a further embodiment, R8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, OCH3, CO2CH3, F, CONH2, CN, and COOH. In still another embodiment, R8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, OCH3, and F. In yet a further embodiment, R8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH and F. In yet another embodiment, R8a is a phenyl ring, optionally substituted with at least 1 OH group.
- In a further embodiment, at least one substituent is in the meta position relative to the position connecting the phenyl ring to the tetrahydroisoquinoline core.
- R8a may also be a 5 or 6-membered heteroaromatic ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, C1-4 alkyl, OC1-4 alkyl, CO2-C1-4 alkyl, halogen, CONH2, CN, and COOH, such as OH, OCH3, CO2CH3, halogen, CONH2, CN, and COOH, particularly OH, OCH3, CO2CH3, F, CONH2, CN, and COOH, more particularly, OH, OCH3, and F, even more particularly OH and F, such as OH. In one embodiment, R8a is optionally substituted pyridinyl, indanyl, dihydro-benzofuranyl, indolinyl or triazolopyrimidinyl. In a further embodiment, R8a is optionally substituted pyridinyl, optionally substituted indanyl, or optionally substituted dihydro-benzofuranyl. In another embodiment, R8a is optionally substituted indanyl or optionally substituted pyridinyl. In yet another embodiment, R8a is pyridinyl.
- R3 is -(CH2)n 3-C(Y3)-(X3)m 3-(CH2)k 3-R3a. In one embodiment, Y3 is O. In a further embodiment, X3 is NH. In another embodiment, Y3 is O and X3 is NH. In a further variation of these embodiments, n3 is 0. In another variation of these embodiments, m3 is 1. In still another variation of these embodiments, n3 is 0 and m3 is 1. In yet another variation of these embodiments, R3a is oxazolyl or pyridinyl, such as oxazol-4-yl or pyridin-4-yl.
- In a different variation of the embodiment, wherein Y3 is O, n3 is 2 and m3 is 0.
- In still a further variation of these embodiments having different variants of R3, k3 is 1.
- R1 is (Ry)k 1-(Y1)n 1-(X1)m 1-Rx, (Ry)k 1-(X1)m 1-(Y1)n 1-Rx or halogen. In one embodiment, R1 is ORx or Y1X1Rx. In a further embodiment, R1 is ORx. In still a further embodiment, R1 is OCH3.
- Y1 is C(O) or S(O)2. In one embodiment, Y1 is C(O).
- X1 is NH or O. In one embodiment X1 is NH.
- k1 is 0 or 1. In one embodiment, k1 is 0.
- n1 is 0 or 1. In one embodiment, n1 is 1.
- m1 is 0 or 1. In one embodiment, n1 is 1.
- Rx is C1-4 alkyl, C2-4alkenyl, C2-4alkynyl or H. In one embodiment, Rx is CH3 or H.
- In a further embodiment, R1 is C(O)NHRx.
- R2 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl,. In one embodiment, R2 is H or O-C1-4 alkyl. In another embodiment, R2 is H.
- R4 is halogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl. In one embodiment, R4 is halogen or C1-2 alkyl. In a further embodiment, R4 is Cl, F, or C1-2 alkyl. In still a further embodiment, R4 is Cl, F, or CH3. In another embodiment, R4 is Cl or CH3. In yet another embodiment, R4 is CH3.
- R5 is hydrogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, OH, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl, each C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl independently optionally substituted with 1 to 3 halogens, such as F. In one embodiment, R5 is H, C1-2 alkyl, or OC1-2 alkyl. In a further embodiment, R5 is C1-2 alkyl or OC1-2 alkyl. In still a further embodiment, R5 is CH3 or OCH3. In yet a further embodiment, R5 is CH3.
- R6 is H, OH, halogen, or NH2. In one embodiment, R6 is H or OH. In a further embodiment, R6 is H.
- R7 is H, halogen, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl. In one embodiment, R7 is H, CH3, or OCH3. In a further embodiment, R7 is H or OCH3. In another embodiment, R7 is H.
- In a particular embodiment of the invention, the compounds of the invention are compounds of Formula II, enantiomers or pharmaceutically acceptable salts thereof:
- In a further embodiment of the invention, the compounds of the invention are compounds of Formula IIa, enantiomers or pharmaceutically acceptable salts thereof:
- In a further particular embodiment of the invention, the compounds of the invention are compounds of Formula III, enantiomers or pharmaceutically acceptable salts thereof:
- In a preferred embodiment, the compound of the invention is selected from the group consisting of compounds 1-63, enantiomers, and pharmaceutically acceptable salts thereof:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 - The compounds of the present invention are intended for use as a medicament. The compounds of the invention may in principle be applied on their own, but they are preferably formulated with a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is an inert carrier suitable for each administration method, and can be formulated into conventional pharmaceutical preparation (tablets, granules, capsules, powder, solution, suspension, emulsion, injection, infusion, etc.). As such a carrier there may be mentioned, for example, a binder, an excipient, a lubricant, a disintegrant and the like, which are pharmaceutically acceptable. When they are used as an injection solution or an infusion solution, they can be formulated by using distilled water for injection, physiological saline, an aqueous glucose solution.
- The administration method of the compounds of the present invention is not particularly limited, and a usual oral or parenteral administration method (intravenous, intramuscular, subcutaneous, percutaneous, intranasal, transmucosal, enteral, etc.) can be applied.
- The dosage of the tetrahydroisoquinoline derivatives or a pharmaceutically acceptable salts thereof of the present invention may optionally be set in a range of an effective amount sufficient for showing a pharmacological effect, in accordance with the potency or characteristics of the compound to be used as an effective ingredient. The dosage may vary depending on administration method, age, body weight or conditions of a patient.
- The compounds of the invention are intended for the treatment of cancer. Hence, in one aspect, the invention concerns a compound or composition according to the invention for use in the treatment of cancer. In particular Ras-driven cancer, Ras genes being the first oncogenes identified in human cancer cells. In one embodiment, the invention concerns a compound or composition according to the invention for use in the treatment of leukemias, lymphomas, myelomas, colorectal cancer, pancreatic cancer, breast cancer and lung cancer, among other types of cancer.
-
-
- At Step 1, ether D is prepared from phenol A by means of a Mitsunobu reaction (reagent B) [G. Liu. et al., Journal of Medicinal Chemistry 2007, 50, 3086-3100] or a nucleophilic substitution reaction (reagent C) under suitable conditions well known in the art. R9 is the protected version of R8 in case R8 contains substituents in need of protection during steps 2, 3, and/or 4. One example of R9 could be a benzyloxy-protected R8, where R8 contains a free OH substituent. Reduction of aldehyde D with sodium borohydride in methanol (step 2) leads to alcohol E which is then converted to alkyl chloride F using thionyl chloride (step 3). At step 4, the substitution reaction of compound F using sodium cyanide as the nucleophile provides nitrile G which is reduced to amine H using H2 and 10% Pd/C as the catalyst (step 5). Hydrogenation of nitrile G additionally involves phenol de-protection of those compounds bearing a protecting group in R9 (Scheme 1b) of an OH group in R8. Since hydrochloric acid is used as an additive in the reaction, the amine H is obtained as the hydrochloride salt. Steps 6-7 involve a well-known Pictet-Spengler reaction [A. Yokohama et al., Journal of Organic Chemistry 1999, 64, 611-617 ; R. Gitto et al., Journal of Medicinal Chemistry 2003, 46, 197-200 ] where arylethylamines H are condensed with different substituted benzaldehydes I to give the corresponding imines J which upon treatment with refluxing trifluoroacetic acid undergo intramolecular cyclization to afford tetrahydroisoquinolines K as racemic mixtures. The Bischler-Napieralski reaction [J. E. De Los Angeles. Journal of Medicinal Chemistry 1996, 39, 3701-3711 ; G. Fodor et al., Angewandte Chemie Int. Ed. 1972, 11, 919-920] is alternatively used to synthesize tetrahydroisoquinolines K bearing an electron-withdrawing group in the R1 or R2 position. At Step 8, the R3 substituent is introduced by means of different synthetic strategies well known in the art.
- Some of the compounds according to the present invention require an alternative synthetic sequence order from that described in the Schemes 1 and 1b. These compounds might be prepared according to Scheme 2 described below.
- At step 1, phenol A is protected using a suitable phenol protecting group PG8, where PG8 may be a benzyl group. Reduction of aldehyde B with sodium borohydride in methanol (step 2) leads to alcohol C which is then converted to alkyl chloride D using thionyl chloride (step 3). At step 4, the substitution reaction of compound D using sodium cyanide as the nucleophile provides nitrile E which is reduced to amine F using H2 and 10% Pd/C as the catalyst (step 5). Since hydrochloric acid is used as an additive in the reaction, the amine F is obtained as a hydrochloride salt. Hydrogenation of nitrile E additionally involves phenol de-protection. Steps 6-7 involve a well-known Pictet-Spengler reaction [A. Yokohama et al., Journal of Organic Chemistry 1999, 64, 611-617 ; R. Gitto et al., Journal of Medicinal Chemistry 2003, 46, 197-200 ] where arylethylamines F are condensed with different substituted benzaldehydes G to give the corresponding imines H which upon treatment with refluxing trifluoroacetic acid undergo intramolecular cyclization to afford tetrahydroisoquinolines I as racemic mixtures. The Bischler-Napieralski reaction [J. E. De Los Angeles. Journal of Medicinal Chemistry 1996, 39, 3701-3711 ; G. Fodor et al., Angewandte Chemie Int. Ed. 1972, 11, 919-920] is alternatively used to synthesize tetrahydroisoquinolines I bearing an electron-withdrawing group in the R1 or R2 position. At step 8, amine I is protected using a suitable protecting group PG3, where PG3 may be a Boc protecting group. Phenol alkylation is carried out in step 9 by means of a Mitsunobu reaction (reagent K) [G. Liu. et al., Journal of Medicinal Chemistry 2007, 50, 3086-3100] or a nucleophilic substitution (reagent L) under suitable conditions well known in the art. At step 10 the amine group of formula M is de-protected under acidic conditions to provide amine N as a hydrochloride salt. At step 11, the R3 substituent is introduced by means of different synthetic strategies well known in the art.
-
- At step 1, 2-(3-bromophenyl)ethanol A is converted to 3-(2-hydroxyethyl)benzonitrile 1 using copper cyanide [referring to the method disclosed in
WO 00/78708 A1 WO 20091055077A1 -
-
- At step 1, compound A is subjected to electrophilic aromatic substitution by means of different synthetic strategies well known in the art. At step 2, amine B reacts with acid C under suitable coupling conditions to give amide D. Steps 3-4 involve a well-known Bischler-Napieralski reaction [J. E. De Los Angeles. Journal of Medicinal Chemistry 1996, 39, 3701-3711 ; G. Fodor et al., Angewandte Chemie Int. Ed. 1972, 11, 919-920] which is used to synthesize tetrahydroisoquinolines F lacking an electron-donating group in the R10 or R2 position. Cyclization of amide D in the presence of phosphorus oxychloride affords dihydroisoquinoline E (step 3) which is subsequently reduced to tetrahydroisoquinoline F at step 4 using sodium borohydride as the reducing agent. Compounds F are obtained as racemic mixtures. At step 5, amine F is protected using a suitable protecting group PG3, where PG3 may be a Boc protecting group. At step 6 the substituent R10, which may be a bromine atom, is converted to the corresponding substituent R11. which may be a CH3OC(O)- group, by means of different synthetic strategies well known in the art. At step 7 the amine group of formula H is de-protected under acidic conditions to provide amine I as a hydrochloride salt. At step 8 the R3 substituent is introduced by means of different synthetic strategies well known in the art. Step 9 involves reaction of compound J with BBr3 at low temperature to afford compound K [
WO 2011/017125 , page 110, step 3]. Phenol alkylation is carried out in step 10 by means of a Mitsunobu reaction (reagent L) [G. Liu. et al., Journal of Medicinal Chemistry 2007, 50, 3086-3100] or a nucleophilic substitution (reagent M) under suitable conditions well known in the art. At step 11 the substituent R11 is converted to the corresponding substituent R1 by means of different synthetic strategies well described in the prior art, which may require different steps depending on the nature of the substituent R1. Hydrogenation of compound O (scheme 4b) involves phenol de-protection of those compounds bearing a protecting group in R9. - When R3 is C(O)NHR3a, i.e. when n3 is 0, Y3 is O, X3 is NH, m3 is 1, and k3 is 0, amine K (Scheme 1) or amine N (Scheme 2) are coupled with R3aNH2 using 1,1-carbonyldiimidazole as coupling agent and a suitable base (e.g. triethylamine) to afford the corresponding ureas L and O respectively [
WO 2015/089337 ]. - When R3=C1-2 alkyl-C(Y3)-(X3)m 3-(CH2)k 3-R3a, i.e. when n3 is 1 or 2, amine L (Scheme 1) or amine O (Scheme 2) are prepared via nucleophilic substitution using Cl-C1-2-alkyl-C(Y3)-(X3)m 3-(CH2)k 3-R3a or Br-C1-2-alkyl-C(Y3)-(X3)m 3-(CH2)k 3-R3a and a suitable base (e.g. triethylamine).
-
- To a solution of 2-(3-Hydroxyphenyl)ethanol (2.2 g, 15.6 mmol) in dry dimethylformamide (40 mL) was added potassium carbonate (4.3 g, 31.1 mmol). After stirring for 10 min at room temperature, benzyl bromide (1.9 mL, 15.6 mmol) was added and the reaction was stirred at 50°C. After 2 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous MgSO4 filtered and concentrated under vacuo to provide the product as a yellow oil (2.7 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.45 (m, 5H), 7.22-7.26 (m, 1H), 6.83-6.87 (m, 3H), 5.06 (s, 2H), 3.88 (t, J=6.2 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
-
- To a solution of 2-(3-(benzyloxy)phenyl)ethanol (1.5 g, 6.6 mmol) in dry tetrahydrofuran (25 mL), 4-hydroxy-3-methoxybenzaldehyde (1.0 g, 6.6 mmol) and triphenylphosphine (2.3 g, 8.5 mmol) were added, followed by the slow addition of diisopropylazodicarboxylate (1.8 mL, 8.5 mmol). The reaction was stirred at room temperature for 2 h. The solvent was evaporated under vacuo and the residue purified by column chromatography on silica gel (Ethyl Acetate:Hexane=20:80) to give the title compound as a white solid (1.7 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.85 (s, 1H), 7.31-7.45 (m, 7H), 7.23 (d, J=7.9 Hz, 1H), 6.94-6.96 (m, 2H), 6.86-6.90 (m, 2H), 5.06 (s, 2H), 4.28 (t, J=7.4 Hz, 2H), 3.93 (s, 3H), 3.17 (t, J=7.4 Hz, 2H).
-
- To a solution of 4-(3-(benzyloxy)phenethoxy)-3-methoxybenzaldehyde (1.7 g, 4.7 mmol) in methanol (93 mL), sodium borohydride (0.7 g, 18.9 mmol) was added in portions. The mixture was stirred at room temperature for 1h. The solvent was evaporated under vacuo and excess reagent remaining in the residue was decomposed with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous MgSO4, filtered and concentrated to give the product as a colourless oil (1.6 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.30-7.45 (m, 5H), 7.21-7.26 (m, 1H), 6.94-6.96 (m, 2H), 6.83-6.90 (m, 4H), 5.06 (s, 2H), 4.62 (d, J=4.8 Hz, 2H), 4.21 (t, J=7.6 Hz, 2H), 3.88 (s, 3H), 3.13 (t, J=7.5 Hz, 2H).
-
- To a solution of (4-(3-(benzyloxy)phenethoxy)-3-methoxyphenyl)methanol (1.6 g, 4.4 mmol) in dry toluene (24 mL), thionyl chloride (0.43 mL, 5.8 mmol) was added dropwise. The mixture was stirred for 45 minutes at room temperature and then refluxed for 1.5 hours. The solvent was evaporated to give the compound as a viscous oil, which was used immediately without purification.
-
- To a solution of 1-(3-(benzyloxy)phenethoxy)-4-(chloromethyl)-2-methoxybenzene (1.7 g, 4.4 mmol) in acetonitrile (72 mL) was added sodium cyanide (0.9 g, 17.8 mmol) and sodium iodide (0.9 g, 6.2 mmol). The reaction was stirred at reflux. After 2 h, the reaction mixture was partitioned between ethyl acetate and water. The extract was dried over anhydrous MgSO4, filtered and the solvent evaporated under vacuo. The residue was purified by column chromatography on silica gel (Ethyl acetate:Hexane=20:80) to give the title compound as a yellow oil (1.2g, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.45 (m, 5H), 7.21-7.25 (m, 1H), 6.94-6.95 (m, 1H), 6.85-6.89 (m, 2H), 6.83 (s, 3H), 5.06 (s, 2H), 4.20 (t, J=7.5 Hz, 2H), 3.87 (s, 3H), 3.69 (s, 2H), 3.13 (t, J=7.5 Hz, 2H).
-
- A solution of 2-(4-(3-(benzyloxy)phenethoxy)-3-methoxyphenyl)acetonitrile (1.2 g, 3.2 mmol) in tetrahydrofuran (12 mL), methanol (35 mL) and concentrated HCl (0.63 mL) was shaken under hydrogen atmosphere (1.5 Atm) at room temperature in the presence of 10% Pd on charcoal (0.24 g, 20% weight). After 24 h the product was isolated by filtering off the catalyst and washing with methanol. The filtrate was evaporated under reduced pressure to give the product as a beige solid (1.0 g, 97% yield) . 1H NMR (400 MHz, CD3OD) δ ppm 7.09 (t, J=7.8 Hz, 1H), 6.89-6.92 (m, 2H), 6.73-6.80 (m, 3H), 6.63 (dd, J=8.1, 1.8 Hz, 1H), 4.16 (t, J=7.0 Hz, 2H), 3.83 (s, 3H), 3.15 (t, J=7.6 Hz, 2H), 2.99 (t, J=7.0 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H).
-
-
- To a solution of 3-(2-(4-(2-aminoethyl)-2-methoxyphenoxy)ethyl)phenol hydrochloride (0.78 g, 2.4 mmol) in methanol (9 mL), triethylamine (2.6 mL, 18.9 mmol) and activated molecular sieves were added followed by the addition of 2,4-dimethylbenzaldehyde (0.35 g, 2.4 mmol) in toluene (15 mL). The reaction was stirred at reflux. After 2h, the reaction mixture was dried over anhydrous MgSO4, diluted with dichloromethane, filtered and concentrated under vacuo to give the crude product which was immediately used as starting material in step B.
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- 3-(2-(4-(2-((2,4-dimethylbenzylidene)amino)ethyl)-2-methoxyphenoxy)ethyl)phenol was mixed with trifluoroacetic acid (25 mL). The reaction was stirred at reflux for 3 h. The reaction mixture was diluted with water and extracted with dichloromethane (x3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under vacuo. The residue was purified by reverse phase chromatography (acetonitrile+0.1% TFA/water+0.1% TFA 0-100% gradient) to give the title product as a beige solid (0.48 g, 39% yield). 1H NMR (400 MHz, CD3OD) δ ppm 7.22 (s, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.02 (t, J=7.9 Hz, 1H), 6.92 (d, J=7.9 Hz, 1H), 6.88 (s, 1H), 6.54-6.61 (m, 3H), 6.20 (s, 1H), 5.84 (s, 1H), 3.93-3.98 (m, 1H), 3.86-3.90 (m, 1H), 3.84 (s, 3H), 3.47-3.58 (m, 2H), 3.20-3.28 (m, 1H), 3.06-3.13 (m, 1H), 2.80-2.83 (m, 2H), 2.48 (s, 3H), 2.34 (s, 3H).
-
- To a suspension of oxazol-4-ylmethanamine dihydrochloride (0.08 g, 0.46 mmol) in dry dimethylformamide (0.3 mL) was added triethylamine (0.13 mL). The mixture was stirred at room temperature for 10 min, after which time was added carbonyldiimidazole (0.04 g, 0.23 mmol). The mixture was stirred at room temperature for 1 h, after which time was added 3-(2-((1-(2,4-dimethylphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)ethyl)phenol 2,2,2-trifluoroacetate (0.06 g, 0.12 mmol) dissolved in dry dimethylformamide (0.7 mL). The reaction was stirred at room temperature. After 4h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water 0-100% gradient) to give the title product as a white solid (0.028 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (s, 1H), 7.56 (s, 1H), 7.08 (t, J=7.8 Hz, 1H), 7.00 (s, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.56-6.71 (m, 5H), 6.35 (s, 1H), 6.29 (s, 1H), 6.11 (bs, 1H), 5.20 (t, J=5.5 Hz, 1H), 4.37 (d, J=5.4 Hz, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.84 (s, 3H), 3.60 (dd, J=14.4, 5.6 Hz, 1H), 3.29 (ddd, J=14.5, 12.4, 4.3 Hz, 1H), 2.91-3.01 (m, 3H), 2.61 (dd, J=16.4, 2.9 Hz, 1H), 2.40 (s, 3H), 2.26 (s, 3H).
- In addition to compound 18, compounds 3, 5-13, 16, 17, 19-22, 25, 26, 29, and 46-53 may also be prepared according to schemes 1 or 1b. Compounds 1, 2, 4, 14, 15, 23 and 54-63 may be prepared according to scheme 2. Compounds 27, 30 and 31 may be prepared according to schemes 2 and 3.
-
- A solution of bromine (1.54 mL, 30 mmol) in dichloromethane (40 mL) was added dropwise to a stirred solution of 2-(4-methoxyphenyl)ethanamine (2.27 g, 15 mmol) in acetic acid (48 mL). After 2 h, the reaction mixture was concentrated under vacuo and the residue purified by reverse phase chromatography (acetonitrile/water 0-100% gradient) to afford the title product (920 mg, 40% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (d, J=1.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.12 (dd, J=7.5, 1.5 Hz, 1H), 5.11 (bs, 2H), 3.83 (s, 3H), 2.98 (t, J=7.1 Hz, 2H), 2.83 (t, J=7.1 Hz, 2H).
-
- 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg, 1.18 mmol) and N,N-diisopropylethylamine (1.03 mL, 5.90 mmol) were added to a solution of 2-(3-bromo-4-methoxyphenyl)ethanamine (226 mg, 0.98 mmol), 2,4-dimethylbenzoic acid (151 mg, 0.98 mmol) and 1-hydroxybenzotriazole hydrate (160 mg, 1.18 mmol) in dry N,N-dimethylformamide. After 24 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water 0-100% gradient) to give the title product as a pale yellow solid (0.32 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.43 (d, J=2.1 Hz, 1H), 7.12-7.20 (m, 2H), 6.95-7.03 (m, 2H), 6.85 (d, J=8.4 Hz, 1H), 5.64-5.78 (m, 1H), 3.88 (s, 3H), 3.65 (dd, J=12.9, 6.8 Hz, 2H), 2.85 (t, J=6.9 Hz, 2H), 2.37 (s, 3H), 2.31 (s, 3H).
-
- Over a solution of N-(3-bromo-4-methoxyphenethyl)-2,4-dimethylbenzamide (0.32 g, 0.88 mmol) in dry acetonitrile (7 mL) was added POCl3 and the mixture was stirred at reflux. After 4 h the reaction mixture was concentrated under vacuo to obtain the crude product (298 mg, 98% yield) which was immediately used without further purification.
-
- To a solution of 6-bromo-1-(2,4-dimethylphenyl)-7-methoxy-3,4-dihydroisoquinoline (298 mg, 0.87 mmol) in methanol (10 mL), sodium borohydride (328 mg, 8.66 mmol) was added in portions. The mixture was stirred at room temperature for 2h. The solvent was evaporated under vacuo and excess reagent remaining in the residue was decomposed with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous MgSO4, filtered and concentrated to give the product as a beige solid (300 mg, 99% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (s, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.92 (dd, J=7.5, 1.5 Hz, 1H), 6.85 (s, 1H), 5.19 (s, 1H), 3.83 (s, 3H), 3.25-3.35 (m, 2H), 2.75-2.79 (m, 2H), 2.34 (s, 6H), 1.91 (bs, 1H).
-
- To a stirred suspension of 6-bromo-1-(2,4-dimethylphenyl)-7-methoxy-3,4-dihydroisoquinoline (300 mg, 0.87 mmol) in water (3.8 mL) was added TEA (0.6 mL, 4.35 mmol) and di-tert-butyl dicarbonate (192 mg, 0.87 mmol) drop by drop at 0°C (ice bath). The mixture was stirred at r.t. for 30 minutes. Then, water was added and the product was extracted with ethyl acetate. The residue was purified by column chromatography on silica gel (Ethyl acetate:Hexane=20:80) to give the title compound as a beige solid (361 mg, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (s, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.92 (dd, J=7.5, 1.5 Hz, 1H), 6.85 (s, 1H), 6.28 (s, 1H), 3.83 (s, 3H), 3.24-3.34 (m, 2H), 2.90-2.93 (m, 2H), 2.34 (s, 6H), 1.38 (s, 9H)
-
- Tert-butyl 6-bromo-1-(2,4-dimethylphenyl)-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg, 0.81 mmol), Pd(dppf)Cl2 (59 mg, 0.08 mmol) and triethylamine (0.34 mL, 2.43 mmol) in methanol (8 mL) were stirred at 100°C under CO atmosphere (100 psi). After 5h the reaction mixture was concentrated under vacuo and the residue purified by column chromatography on silica gel (Ethyl acetate:Hexane=20:80) to give the title compound as a beige solid (300 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.07 (s, 1H), 6.92-6.98 (m, 3H), 6.28 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.24-3.34 (m, 2H), 2.90-2.93 (m, 2H), 2.34 (s, 6H), 1.38 (s, 9H).
-
- Over a solution of 2-tert-butyl 6-methyl 1-(2,4-dimethylphenyl)-7-methoxy-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate (300 mg, 0.70 mmol) in dioxane (1.2 mL) was added a solution of HCl 4.0 M in dioxane (4 mL, 16.8 mmol). The reaction mixture was stirred at 55°C. After 2h the solvent was evaporated under vacuo to yield the crude product as a chlorhydrate salt (252 mg, 100% yield). 1H NMR (400 MHz, CD3OD) δ ppm 7.59 (s, 1H), 7.07 (s, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.92 (dd, J=7.5, 1.5 Hz, 1H), 5.19 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.25-3.35 (m, 2H), 2.75-2.79 (m, 2H), 2.34 (s, 6H).
-
- To a suspension of oxazol-4-ylmethanamine dihydrochloride (398 mg, 2.81 mmol) in dry dimethylformamide (2 mL) was added triethylamine (0.78 mL, 5.6 mmol). The mixture was stirred at room temperature for 10 min, after which time was added carbonyldiimidazole (257 mg, 1.4 mmol). The mixture was stirred at room temperature for 1 h, after which time was added methyl 1-(2,4-dimethylphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (252 mg, 0.70 mmol) dissolved in dry dimethylformamide (3.8 mL). The reaction was stirred at room temperature. After 4h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water 0-100% gradient) to give the title product as a white solid (189 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.07 (s, 1H), 6.92-6.98 (m, 3H), 6.28 (s, 1H), 6.01 (bs, 1H), 4.10 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.44-3.54 (m, 2H), 2.90-2.93 (m, 2H), 2.34 (s, 6H).
-
- To a solution of methyl 1-(2,4-dimethylphenyl)-7-methoxy-2-((oxazol-4-ylmethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (189 mg, 0.42 mmol) in anhydrous dichloromethane (2.3 mL) was added boron tribromide 1.0 M in methylene chloride (0.84 mL, 0.84 mmol) dropwise at -78°C. The reaction mixture was stirred overnight at room temperature and quenched by ice. The resulting mixture was extracted by ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to yield the product as a brown solid (135 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 6.92-7.03 (m, 4H), 6.28 (s, 1H), 6.01 (bs, 1H), 5.35 (bs, 1H), 4.10 (s, 2H), 3.89 (s, 3H), 3.44-3.54 (m, 2H), 2.90-2.93 (m, 2H), 2.34 (s, 6H).
-
- To a solution of 2-(pyridin-3-yl)ethanol (38 mg, 0.31 mmol) in dry tetrahydrofuran (1.2 mL), methyl 1-(2,4-dimethylphenyl)-7-hydroxy-2-((oxazol-4-ylmethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (135 mg, 0.31 mmol) and triphenylphosphine (107 mg, 0.4 mmol) were added, followed by the slow addition of diisopropylazodicarboxylate (84 µL, 0.4 mmol). The reaction was stirred at room temperature for 2 h. The solvent was evaporated under vacuo and the residue purified by column chromatography on silica gel (Ethyl Acetate:Hexane=20:80) to give the title compound as a white solid (90 mg, 54% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.41-8.43 (m, 2H), 7.95 (s, 1H), 7.67-7.69 (m, 2H), 7.59 (s, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.07 (s, 1H), 6.92-6.98 (m, 3H), 6.28 (s, 1H), 6.01 (bs, 1H), 4.27 (t, J=7.1 Hz, 2H), 4.10 (s, 2H), 3.89 (s, 3H), 3.44-3.54 (m, 2H), 2.93-3.00 (m, 4H), 2.34 (s, 6H).
-
- Over a solution of methyl 1-(2,4-dimethylphenyl)-2-((oxazol-4-ylmethyl)carbamoyl)-7-(2-(pyridin-3-yl)ethoxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (90 mg, 0.166 mmol) in THF (8.3 mL) and water (830 µL), lithium hydroxide (8 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature. After 2h water (8 mL) was added to dilute the reaction mixture, the organic solvent was evaporated under vacuo and the aqueous residue was acidified (pH=5) by addition of 1N HCl. Extraction with ethyl acetate was carried out to obtain the product as clorhydrate salt (90 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ ppm 11.0 (bs, 1H), 8.41-8.43 (m, 2H), 7.95 (s, 1H), 7.75 (s, 1H), 7.67-7.69 (m, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.17 (s, 1H), 6.92-6.98 (m, 3H), 6.28 (s, 1H), 6.01 (bs, 1H), 4.27 (t, J=7.1 Hz, 2H), 4.10 (s, 2H), 3.44-3.54 (m, 2H), 2.90-3.00 (m, 4H), 2.34 (s, 6H).
-
- 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) and N,N-diisopropylethylamine (84 µL, 0.48 mmol) were added to a solution of ammonium chloride (43 mg, 0.8 mmol), 1-(2,4-dimethylphenyl)-2-((oxazol-4-ylmethyl)carbamoyl)-7-(2-(pyridin-3-yl)ethoxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride (90 mg, 0.16 mmol) and 1-hydroxybenzotriazole hydrate (22 mg, 0.16 mmol) in dry N,N-dimethylformamide. After 24 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water 0-100% gradient) to give the title product as a white solid (49 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.41-8.43 (m, 2H), 7.95 (s, 1H), 7.67-7.69 (m, 2H), 7.57 (s, 1H), 7.50 (bs, 2H), 7.25 (t, J=7.5 Hz, 1H), 6.92-6.98 (m, 3H), 6.28 (s, 1H), 6.01 (bs, 1H), 4.27 (t, J=7.1 Hz, 2H), 4.10 (s, 2H), 3.44-3.54 (m, 2H), 2.90-3.00 (m, 4H), 2.34 (s, 6H).
- In addition to compound 34, compounds 24, 28, 32, 33 and 35-45 may also be prepared according to schemes 4 or 4b.
-
- Cell line #1: A549. Lung carcinoma cell line bearing KRasG125 oncogenic mutation
- Cell line #2: H358. non-small cell lung cancer line bearing KRasG12C oncogenic mutation
- Cell line #3: PANC-1. epithelioid carcinoma of the pancreas cell line bearing KRasG12D oncogenic mutation
- Cell line #4: RPMI. myeloma cell line bearing KRasG12A oncogenic mutation
- Cell lines were cultured in DMEM or RPMI-1640 supplemented with FBS 10%. In order to assess the antiproliferative effect of compounds, cells were seeded at a density of 1.8x103, 6.2 x103, 7.8 x103, 21 x103 and 2x103 cells/cm2, respectively, in tissue culture microplates and were incubated in humidified atmosphere at 5% CO2. 24h later, compounds dissolved in DMSO 100% were added for different final concentrations ranging between 0.1 and 50 µM for a final DMSO concentration of 0.5% and the plates were incubated for another 72 h. After incubation, proliferation was quantified using CellTiter 96® Aqueous Non-Radioactive Cell Proliferation Assay-MTS (Promega #G5421) following manufacturer instructions. Amount of 490nm absorbance is directly proportional to the number of living cells. Absorbance was recorded with a BMG Fluostar Optima Microplate Reader and normalized to control with vehicle.
IC50 values (µM): cell proliferation inhibition Compound A549 RPMI-8226 H358 PANC-1 1 11.73 2.17 18.31 17.26 2 8.25 1.8 12.12 17.29 3 1.97 1.21 1.66 1.59 4 10.09 2.67 >20 29.67 5 4.82 1.51 >20 >30 6 9.09 5.65 19.94 24.72 7 6.34 2.41 18.1 24.77 8 4.11 2.11 11.22 11.11 9 3.65 0.74 18.95 24.50 10 15.87 0.86 19.76 15.03 11 18.03 1.47 8.52 12.27 12 8.99 4.98 16.82 13.59 13 9.37 2.86 15.75 12.59 14 >10 3.94 >10 >30 15 2.14 0.89 2.58 2.13 16 >5 0.48 7.24 11.97 17 3.52 1.74 3.10 1.83 18 1.97 1.21 1.66 1.59 19 0.95 2.93 0.68 0.57 20 0.75 0.60 0.48 0.56 21 1.33 0.90 0.78 0.81 22 0.89 0.82 0.65 0.60 23 0.55 0.62 0.59 0.49 24 0.74 0.87 0.84 0.66 25 0.55 0.58 0.52 0.53 26 2.02 0.79 1.01 1.15 27 1.02 0.98 1.12 1.33 28 1.56 1.02 1.23 2.01 29 0.76 0.69 0.96 0.68 30 1.47 1.21 1.41 2.11 31 2.07 1.91 2.11 1.83 32 0.44 0.52 0.31 0.49 33 1.57 1.31 1.04 2.03 34 0.43 0.72 0.39 0.42 35 0.33 0.32 0.51 0.43 36 0.73 0.99 0.91 0.67 37 0.81 1.21 0.71 0.74 38 0.43 0.22 1.09 0.42 39 0.34 0.41 0.52 0.47 40 0.82 1.33 0.96 0.81 41 1.27 1.38 1.14 2.11 42 0.49 0.32 1.21 0.62 43 0.74 0.61 0.91 0.88 44 1.72 0.99 1.01 1.00 45 0.79 0.89 0.99 0.87 46 0,6 0,5 0,7 0,7 47 1,5 1,5 1,2 1,5 48 0,7 0,9 0,8 0,7 49 >1 >1 >1 >1 50 0,8 0,8 0,8 0,5 51 0,5 0,6 0,6 0,5 52 0,6 0,7 0,6 0,5 53 0,6 0,5 0,7 0,7 54 0,6 0,5 0,7 0,7 55 0.6 0.6 0.6 0.5 56 0.6 0.6 0.6 0.5 57 0.6 0.6 0.6 0.5 58 0.6 0.6 0.6 0.5 59 0,6 0,5 0,7 0,7 60 0,6 0,5 0,7 0,7 61 0,6 0,5 0,7 0,7 62 0,6 0,5 0,7 0,7 63 0,6 0,5 0,7 0,7 - Data shown for compounds 1-53 are the median from experimental results. Data shown for compounds 54-63 are based on estimations and/or preliminary experimental results.
- Evaluation of the Efficacy of compound 18 in the Treatment of Subcutaneous NCI-H358 Human Lung Cancer Xenograft Model in NOD/SCID Mice
- The treatments were started when the mean tumor size reached 141mm3. The test article administration and the animal numbers in each study group are shown in the following experimental design table.
Group N Treatment Dose (mg/kg) Dosing Schedule 1 6 Vehicle Control - i.p. Bid x 22day 2 6 Compound 18 10 i.p. Bid x 22day 3 6 cisplatin 3.5 i.p. BIW x 3.5week - Note:
- N: animal number;
- Dosing volume: 10 µl/g
- Study endpoints: The major endpoints of the study included the followings:
Tumor growth inhibition (TGI): TGI(%) is an indication of antitumor effectiveness, and expressed as: TGI (%)=100 × (1-T/C). T and C were the mean tumor volume of the treated and control groups, respectively, on a given day. - The results of the body weight changes in the tumor bearing mice are shown in
Figure 1 . The body weight loss (BWL) of just one mouse reached 10% in group 2 (compound 18, 10 mg/kg), while the BWL of 4 mice in group 3 (Cisplatin, 3.5 mg/kg) reached 10% or even lower. The results suggest that the mice bearing the subcutaneous NCI-H358 human lung cancer xenograft model tolerate 10 mg/kg b.i.d of Compound 18. - The tumor growth curves of the different groups are shown in
Figure 2 . - The mean tumor volume of group-1 (vehicle) reached 630mm3 on Day 24 after inoculation (PG-D22, Day 22 after first-dosing). The mean tumor volume of group-2 (Compound 18, 10 mg/kg) reached 238mm3 on PG-D22, and TGI is about 62%. The mean tumor volume of group-3 (Cisplatin, 3.5mg/kg) reached 231mm3 on PG-D22, and TGI is about 63%. Compared with the vehicle group, groups 2 and 3 both exhibit significant anti-tumor effects (group-2 p=0.026, group-3 p=0.019).
- The test compound 18 demonstrated significant anti-tumor activities in subcutaneous NCI-H358 human lung cancer xenograft model, and 10mg/kg b.i.d. of compound 18 is safe for the bearing mice.
- The KD for Compound 18 is 8.8 nM (Ka= 1.17x105 M-1·s-1; Kd=1.03×10-3s-1)
- Various concentrations of KRas dissolved in water were manually printed onto bare gold-coated (thickness 47 nm) PlexArray Nanocapture Sensor Chips (Plexera Bioscience, Seattle, WA, US) at 40% humidity. Each concentration was printed in replicate, and each spot contained 0.2 µL of KRas solution. The chip was incubated in 80% humidity at 4°C for overnight, and rinsed with 10× PBST for 10 min, 1× PBST for 10 min, and deionized water twice for 10 min. The chip was then blocked with 5% (w/v) non-fat milk in water overnight, and washed with 10× PBST for 10 min, 1× PBST for 10 min, and deionized water twice for 10 min before being dried under a stream of nitrogen prior to use. SPRi measurements were performed with PlexAray HT (Plexera Bioscience, Seattle, WA, US). Collimated light (660 nm) passes through the coupling prism, reflects off the SPR-active gold surface, and is received by the CCD camera. Buffers and samples were injected by a non-pulsatile piston pump into the 30 µL flowcell that was mounted on the coupling prim. Each measurement cycle contained four steps: washing with PBST running buffer at a constant rate of 2 µL/s to obtain a stable baseline, Compound 18 injection at 5 uL/s for binding, surface washing with PBST at 2 µL/s for 300 s, and regeneration with 0.5% (v/v) H3PO4 at 2 µL/s for 300 s. All measurements were performed at 4°C. The signal changes after binding and washing (in AU) are recorded as the assay value. Selected protein-grafted regions in the SPR images were analyzed, and the average reflectivity variations of the chosen areas were plotted as a function of time. Real-time binding signals were recorded and analyzed by Data Analysis Module (DAM, Plexera Bioscience, Seattle, WA, US). Kinetic analysis was performed using BIAevaluation 4.1 software (Biacore, Inc.).
- The protocol to perform 3D CellTiter-GloTM cell viability assay is as follows:
- Day -1: Cell plating
- Adjust cell concentrations to 1×105 cells/ml with respective medium. (Cell concentration is adjusted according to data base or density optimization assay). Mix 3.5 mL of cell suspension 6.5 mL of 1% methylcellulose. Mix and wait for bubbles to disperse before pipetting. This step yields 10 ml of cell suspension in 0.65% methylcellulose solution. Add 99.5 µL cell suspensions to 96-well plates according to plate map with final cell density.
- Two duplicate plates will be set up. One is for day 0 reading (T0) and the other will be cultured in incubator for reading at the end point.
- Incubate the plates overnight in humidified incubator at 37° C with 5% CO2.
- Day 0: T0 plate reading and compound treatment
- Take T0 plate, add 0.5 µL culture medium to each well for T0 reading.
- Add 100 µl CellTiter-Glo® Reagent to each well.
- Mix contents for 2 minutes on an orbital shaker to facilitate cell lysis.
- Allow the plate to incubate at room temperature for 10 minutes to stabilize luminescent signal.
- Record luminescence using EnVision Multi Label Reader.
- Dilute the test articles at the concentration indicated at Test Articles Dilution. Add 0.5 µL of each 200X compound working solutions according to plate inoculation map.
- Day 7: Plate reading of 7 days' compound treatment
- Add 100 µL CellTiter-Glo® Reagent to each well.
- Mix contents for 2 minutes on an orbital shaker to facilitate cell lysis.
- Allow the plate to incubate at room temperature for 10 minutes to stabilize luminescent signal.
- Record luminescence using EnVision Multi Label Reader.
Compound | IC50 (µM) |
17 | 0,62 |
18 | 0,37 |
23 | 0,39 |
26 | 9,351 |
42 | 10,057 |
46 | 0,842 |
48 | 0,917 |
50 | 0,373 |
51 | 0,334 |
Claims (15)
- A compound of Formula I, enantiomers and pharmaceutically acceptable salts thereof:R1 is (Ry)k 1-(Y1)n 1-(X1)m 1-Rx, (Ry)k 1-(X1)m 1-(Y1)n 1-Rx or halogen,Y1 is C(O) or S(O)2,X1 is NH or O,Ry is C1-4 alkanediyl, C2-4alkenediyl or C2-4 alkynediyl,Rx is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or H;k1 is 0 or 1,n1 is 0 or 1,m1 is 0 or 1,R2 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl;R3 is -(CH2)n 3-C(Y3)-(X3)m 3-(CH2)k 3-R3a,n3 is an integer in the range of 0 to 2,Y3 is S or O,X3 is S, NH, or O,m3 is 0 or 1,k3 is 0 or 1,R3a is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl Het3, Ar3, HetCyc3 or Cyc3,Het3 is a 5- to 10-membered heteroaromatic ring or ring system containing one or more heteroatoms selected from the group consisting of N, O, and S,Ar3 is a 6- to 10-membered aromatic ring or ring system,HetCyc3 is a 3- to 8-membered heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S,Cyc3 is a 3- to 8-membered cyclyl;R4 is halogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl;R5 is hydrogen, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, OH, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl, each C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl independently optionally substituted with 1 to 3 halogens;R6 is H, OH, halogen, or NH2;R7 is H, halogen, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, or OC2-4 alkynyl;R8 is -(CH2)n 8-(C(O))m 8-R8a,n8 is an integer from 1 to 2, m8 is an integer from 0 to 1, andR8a is an aromatic or heteroaromatic ring having 5 or 6 ring members, optionally substituted with at least 1 substituent selected from the group consisting of OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OC1-4 alkyl, OC2-4 alkenyl, OC2-4 alkynyl, CO2-C1-4 alkyl, CO2-C2-4 alkenyl, CO2-C2-4 alkynyl, halogen, CONH2, CN, COOH, -OCO-C1-4 alkyl, -OCO-C2-4 alkenyl, -OCO-C2-4 alkynyl, -NHCO-C1-4 alkyl, -NHCO-C2-4 alkenyl, -NHCO-C2-4 alkynyl, NH2, NHC1-4 alkyl, NHC2-4 alkenyl, NHC2-4 alkynyl, N(C1-4 alkyl)2, N(C2-4 alkenyl)2, N(C2-4 alkynyl)2, CONHC1-4 alkyl, CONHC2-4 alkenyl, CONHC2-4 alkynyl, CON(C1-4 alkyl)2, CON(C2-4 alkenyl)2, CON(C2-4 alkynyl)2; or R8a is an aromatic or heteroaromatic ring having 5 or 6 ring members fused with an additional optionally substituted cyclic, heterocyclic, aromatic, or heteroaromatic ring.
- The compound according to claim 1 wherein:
R8a is a phenyl ring, optionally substituted with at least 1 substituent selected from the group consisting of OH, C1-4 alkyl, OC1-4 alkyl, CO2-C1-4 alkyl, halogen, CONH2, CN, and COOH, preferably OH, OCH3, CO2CH3, F, CONH2, CN, and COOH, more preferably, OH, OCH3, and F, even more preferably OH and F. - The compound according to claim 2, wherein the phenyl ring is substituted in the meta position.
- The compound according to claim 1, wherein R8a is optionally substituted pyridinyl, indanyl, 2,3-dihydro-benzofuran-5-yl, or pyrymidino[1,2-b][1,2,4]triazol-3-yl.
- The compound according to any one of claims 1 to 4, wherein Y3 is O and X3 is NH.
- The compound according to claim 5, wherein n3 is 0 and m3 is 1.
- The compound according to any one of claims 5 or 6, wherein R3a is oxazolyl or pyridinyl, preferably oxazol-4-yl or pyridin-4-yl.
- The compound according to any one of claims 1 to 4, wherein n3 is 2 and m3 is 0.
- The compound according to any one of claims 5 to 8, wherein k3 is 1.
- The compound according to any one of claims 1 to 9, wherein R2 is H.
- The compound according to any one of claims 1 to 10, wherein R6 and R7 are H.
- A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.
- The compound according to any one of claims 1 to 12 or the composition according to claim 13 for use as a medicament.
- The compound according to any one of claims 1 to 12 or the composition according to claim 13 for use in the treatment of cancer.
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AU2021344830A1 (en) | 2020-09-03 | 2023-04-06 | Revolution Medicines, Inc. | Use of SOS1 inhibitors to treat malignancies with SHP2 mutations |
WO2023169481A1 (en) * | 2022-03-09 | 2023-09-14 | 思路迪生物医药(上海)有限公司 | Tetrahydroisoquinoline derivative as pan-kras inhibitor, preparation method therefor and use thereof |
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SE0303542D0 (en) * | 2003-12-22 | 2003-12-22 | Astrazeneca Ab | 1,2,3,4-Tetrahydroisoquinoline derivatives, preparations thereof and uses thereof |
ZA200701232B (en) * | 2004-07-15 | 2008-08-27 | Amr Technology Inc | Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin |
CA2661462C (en) | 2006-08-23 | 2015-09-29 | Valeant Pharmaceuticals International | Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators |
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